The Acute Liver Failure Study Group (ALFSG) was developed on the premise that a network of sites acting in concert was the only way to impact this rare condition by providing enough patients for detailed study and clinical trials. Since 1998, the group has collected and disseminated important clinical information and bio- samples on more than 1,600 patients and conducted a randomized controlled trial of N-acetylcysteine for non-acetaminophen acute liver failure (ALF). Among its accomplishments, ALFSG has provided new insights into the central role of acetaminophen (APAP) in ALF in United States patients and further characterized many of the other etiologies such as hepatitis A, hepatitis B, autoimmune hepatitis and ischemic liver disease as well as focusing on disease outcomes and the role of transplantation. More than 70 ancillary studies have been initiated utilizing our data and bio-samples, generating 37 original articles on all aspects of ALF. A recent addition was the Acute Liver Injury (ALI) study, capturing earlier stage disease, prior to the onset of advanced liver failure. Our plan for the future rests on our ability to continue the ALF registry while simultaneously addressing more basic mechanistic studies and performing additional therapy trials. Recent innovations within the group that will impact our functioning in the future include reducing the number of sites to our top participating centers, adopting electronic data capture and the collection of more detailed clinical information on our cases. Planned approaches for the future include more deliberate studies of genomics, cytokines, coagulation and hepatic regeneration, as well as the conduct of at least two clinical trials of new agents for treatment of this dreaded condition.